Intravenous administration of monoclonal antibodies leads to low concentrations in the central nervous system, which is a serious concern in neuro‐oncology, especially in leptomeningeal carcinomatosis of HER2‐overexpressing breast cancer. Case reports of i.t. administrations of trastuzumab have shown promising results in these patients but dosing regimens are empirical in absence of pharmacokinetic (PK) study. With a population PK approach, we described the fate of trastuzumab after i.t. administration in 21 women included in a phase I–II clinical trial. Trastuzumab was administered by i.t. route every week for 8 weeks and both cerebrospinal fluid (CSF) and serum were sampled to measure trough concentrations. Some patients showed noticeable CSF concentration fluctuations predicted using a target‐mediated drug disposition. This target was latent and produced with a delayed feedback. Apparent volumes of distribution were close to physiological volumes (V1 = 3.25 L, V2 = 0.644 L, for serum and CSF, respectively). Estimated (constant) transfer from serum to CSF was very slow (k12 = 0.264 mg/day) whereas estimated half‐life of transfer from CSF to serum was rapid (2.2 days). From the individual parameters of patients, a single i.t. administration of 150 mg of trastuzumab corresponded to median mean residence times of 3.8 days and 15.6 days in CSF and serum, respectively. Survival without neurological relapse was not related to trastuzumab exposure. This study confirms that transfer of trastuzumab from serum to CSF is very limited and that this monoclonal antibody, when administered by i.t. route, is rapidly transferred to the serum.